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Category: genetics

Hidden mosquito viruses emerge as RNA immune signals map global infections

Aedes aegypti, commonly known as the yellow fever mosquito, is a highly adapted, invasive mosquito species recognized as a major global health threat that acts as the primary vector for several severe diseases, most notably dengue fever, as well as yellow fever, chikungunya and Zika virus. Local government agencies conduct routine molecular surveillance of these mosquitoes to detect and track viruses. However, they are primarily limited to using conventional reverse transcription polymerase chain reaction methodologies, which can only detect known pathogens that have already been identified and for which specific genetic primers have been developed.

Recent research efforts applying high-throughput RNA sequencing have led to a large expansion in the mosquito virome (the entire collection of viruses contained within mosquitoes). However, questions remain as to how persistent insect viruses are within mosquito colonies, how insect viruses interact with mosquito immune responses and how frequently insect viruses can be transmitted.

A new study by Boston University Chobanian & Avedisian School of Medicine researchers looked at the mosquitoes’ immune response to discover many more insect viruses and they hope to someday use the mosquitoes’ own immune system to battle some of the most pervasive and antagonistic human viruses. The findings are published in the journal Nature Communications.

Vitamin D Receptor Polymorphisms and Diabetes Risk

Among adults with Prediabetes, vitamin D3 supplementation was associated with lower diabetes risk only in those with specific ApaI vitamin D receptor genotypes.

This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4,000 IU/d of vitamin D3 supplementation among adults with prediabetes. Participants carrying the ApaI AA genotype did not experience a reduction in diabetes risk, either when achieving higher intratrial 25(OH)D concentrations or while being treated with 4,000 IU/d of vitamin D3. In contrast, those carrying the ApaI CC and AC genotypes, representing 71% of the D2d study population, had progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/mL or higher. Participants with these genotypes randomized to vitamin D3 had a 19% reduction in the risk of progression to diabetes compared with placebo, whereas those with ApaI AA alleles did not respond to treatment with vitamin D3. The BsmI polymorphism also appeared to play a role in the association between the achieved intratrial 25(OH)D level and diabetes risk, as expected given the high linkage disequilibrium of ApaI and BsmI (D’ = 1.0 and r2 = 1.0) among people of European ancestry.15 Because there was a near complete overlap between participants carrying the nonresponsive Bsml TT genotype and those carrying the nonresponsive ApaI AA genotype, knowing the ApaI genotype alone was sufficient to identify individuals who were likely—or unlikely—to respond to supplementation with 4,000 IU/d of vitamin D3. These exploratory genetic association findings support our hypothesis that a common VDR variant modulates the link between high intratrial 25(OH)D levels and diabetes risk, and the association between relatively high-dose vitamin D3 supplementation and diabetes risk among adults with prediabetes. The distributions of alleles of the 3 polymorphisms in the D2d study were similar to those reported in the UK Biobank of participants with prediabetes.5 Consistent with the UK Biobank study and other studies,5,16,17 the 25(OH)D levels achieved during the D2d trial did not differ significantly among participants with different VDR polymorphisms.

In the UK Biobank study, among adults with prediabetes and a median 25(OH)D level of 19.2 ng/mL (a value below our referent range of 20–29.9 ng/mL), there was a stepwise decrease in the risk of diabetes at 25(OH)D levels of lower than 10 (the study’s referent), 10 to 20, 20 to 30, and 30 ng/mL or higher.5 Risk reduction was present in all VDR genotypes of the 4 examined polymorphisms (ApaI, BsmI, TaqI, and FokI), but it was more prominent among those carrying the T allele of BsmI. There were too few participants in the D2d study with sufficiently low 25(OH)D levels to address this range of the 25(OH)D spectrum. Conversely, there were too few participants with sufficiently high 25(OH)D levels in the UK Biobank study to address the question posed in our study. To our knowledge, no other high-dose vitamin D trials among adults with prediabetes have examined how VDR polymorphisms may modify the effect of vitamin D supplementation on diabetes risk.

Our exploratory findings, if confirmed, hold promise for high-dose vitamin D3 as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes. The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes. In the original report of the D2d trial,2 the HR for conversion to type 2 diabetes with vitamin D supplementation was 0.88 (95% CI, 0.72−1.04). The HR decreased to 0.81 (95% CI, 0.66−0.99) in our exploratory analysis when genetically nonresponsive participants (those with AA alleles of the ApaI polymorphism, comprising 29.5% of all participants) were excluded. If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D3 supplementation would not be trivial. First, assessment of a single VDR polymorphism is inexpensive and now widely available.

Multicentre gene therapy for OTOF-related deafness followed up to 2.5 years

A new international study co-led by investigators from Mass General Brigham and the Eye & ENT Hospital of Fudan University shows that a gene therapy for a rare form of genetic deafness successfully restored hearing in most participants, with results lasting up to 2.5 years. The results, the largest clinical trial of gene therapy for inherited hearing loss to date and the longest follow-up reported so far, are published in Nature. According to the authors, these latest findings reinforce earlier trials that show gene therapy can be used to treat some forms of inherited deafness, helping guide future research and care.

“It’s remarkable to see patients go from complete deafness to being able to hear,” said the study’s corresponding author, Zheng-Yi Chen, DPhil, the Ines and Fredrick Yeatts Chair in Otolaryngology and an associate scientist at Mass Eye and Ear, a member of the Mass General Brigham healthcare system. “For many patients, that also means the ability to develop and use speech.”

Genetic mutations account for up to 60% of hearing loss present at birth. In this study, researchers used a gene therapy they developed to treat autosomal recessive deafness 9 (DFNB9), caused by mutations in the OTOF gene. The OTOF gene provides the body with instructions to make a protein called otoferlin, which is essential for hearing function. Without it, hair cells in the inner ear cannot pass sound signals to the brain, causing severe-to-complete deafness at birth. OTOF mutations account for about 2 to 8 in every 100 cases.

Gene therapies are designed to add a working version of mutated genes that lead to disease. Since a single faulty gene causes DFNB9, it is well-suited for gene therapy research. The treatment is a single injection into the inner ear that uses a harmless virus (AAV) to deliver a working copy of the OTOF gene to the cells needed for hearing.

This latest trial enrolled 42 participants across eight sites in China, ranging in age from infants to adults (0.8 to 32.3 years). Each participant received one of three doses of a single gene therapy treatment: 36 in one ear and six in both ears. The research team then followed participants for up to 2.5 years, to see if treatment remained safe, affected their hearing and speech recognition. The researchers also sought to better understand why some participants may respond better than others.

“These multicenter trial results validate the effectiveness of our OTOF gene therapy,” said Yilai Shu, MD, PhD, a professor from Eye & ENT Hospital of Fudan University, who led the study. “The procedure can be broadly implemented in hospital settings, ensuring consistent delivery for a larger patient population.”

Abstract: Multicentre gene therapy for OTOF-related deafness followed up to 2.5 years https://www.nature.com/articles/s41586-026-10393-y.

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Immune molecule long tied to inflammation may benefit the aging brain

Inflammation in the brain is usually seen as harmful in the aging process—it’s thought to contribute to Alzheimer’s and dementia. But a new study in mice suggests that inflammation, led by an immune molecule called STING (stimulator of interferon genes), might have a role in protecting the aging brain. The findings also have implications for new experimental Alzheimer’s drugs that are designed to block STING.

For the study published in Cell Reports, scientists at Tufts University School of Medicine examined brain function, inflammation, and movement in genetically engineered to lack STING, compared with normal controls. They found that mice without STING had worse memory and movement problems, mimicking the senility and frailty seen in people with dementia and Alzheimer’s disease.

“Our data suggest that the that STING supports may actually be necessary for the brain to stay healthy and in balance during old age,” says Shruti Sharma, an assistant professor of immunology at Tufts University School of Medicine and the study’s senior author.

A skin-hypothalamus axis couples heat stress and metabolic dysfunction

Now online! Heat stress activates a skin-hypothalamus axis via KLK14-dependent epigenetic reprogramming of LRRC7⁺ astrocytes, thereby exacerbating diet-induced metabolic dysfunction. Vitamin A reduces KLK14 levels and mitigates metabolic impairment in both mice and humans.

A hidden DNA region helps drive frailty, exposing brain and immune links that reshape aging risk

Researchers at McMaster University have identified, for the first time, a novel region of DNA and two associated genes connected to frailty, offering neurological and immune-related insights that might help explain why some older adults are more likely to be frail than others.

The McMaster team’s findings, published in the journal npj Aging, fill an important gap by revealing genetic factors that contribute to the development of frailty. The discovery provides a biological connection to the condition and points toward new avenues for early detection and targeted intervention.

Stem cell gene editing to produce B cell protein factories

As a proof of concept, the team used CRISPR gene-editing tools to insert the genetic blueprint for producing rare, protective antibodies directly into hematopoietic stem and progenitor cells of mice. Once transplanted back into mice, the edited stem cells gave rise to B cells programmed to produce the engineered antibody. A conventional vaccination would then serve as the trigger.

It worked. Even when only a few dozen stem cells were edited, vaccination triggered rare cells to expand, mature into plasma cells, and produce large amounts of antibodies that persisted long-term and could be boosted if necessary. The engineered B cells behaved just like normal immune cells, and even provided protection from disease. Mice engineered to produce a broadly neutralizing influenza antibody were spared from an otherwise lethal influenza infection.

The team went on to demonstrate their novel platform’s versatility. Engineered B cells were able to secrete non-antibody proteins, pointing to potential applications in treating genetic diseases caused by missing enzymes or other essential proteins.

The researchers also showed that stem cells carrying different antibody instructions could be combined, enabling a single immune system to produce multiple antibodies at once—an approach that could limit viral escape and ultimately lead to functional cures for rapidly mutating pathogens such as HIV.

And the team showed that human stem cells edited using the same approach gave rise to functional immune cells, providing a key proof of feasibility that the platform could one day work in humans, as well. Science Mission sciencenewshighlights.

An innovative gene-editing strategy could establish a new way for the body to manufacture therapeutic proteins—including certain kinds of highly potent antibodies the are naturally difficult to produce—by reprogramming the immune system itself.

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